RecQ dysfunction contributes to social and depressive-like behavior and affects aldolase activity in mice

RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target

Experimental and Numerical Investigation of Temperature Development of Ohmic Heating Cured Nonmass Concrete under Subzero Temperature

In this paper, carbon fiber/carbon nanofiber strengthening nonmass concrete slab was designed, and ohmic heating (OH) curing was used to promote the strength formation of the slab under −20°C. COMSOL multiphysical field coupling program has been used to simulate the heating process of nonmass concrete slabs under different conditions. COMSOL analysis results showed that the optimal loading power density of OH cured sample under −20°C was 1000 W/m2∼1200 W/m2. Moreover, numerical analysis results were experimentally validated by the multipoint temperature measurement method. Furthermore, the mechanical properties showed that the compressive strength of the sample cured by 2 days OH curing at −20°C reached up to 48.2 MPa. SEM analysis exhibited that OH curing could improve the interfacial transition zone (ITZ) between the fiber and the matrix, leading to a denser microstructure. This study proved that COMSOL program could provide good theoretical guidance for OH cured nonmass cement concrete under subzero temperature. This work establishes an accurate guideline for electric power supplementation, laying a solid foundation of winter construction with high efficiency and low energy consumption

NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD(+)) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD(+) are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD(+) precursor nicotinamide riboside (NR) for 5 mo increased brain NAD(+) levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS–STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS–STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD(+) depletion-mediated activation of cGAS–STING in neuroinflammation and cellular senescence in AD

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.publishe

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease

Alzheimer disease (AD) is a devastating neurological disease associated with progressive loss of mental skills and cognitive and physical functions whose etiology is not completely understood. Here, our goal was to simultaneously uncover novel and known molecular targets in the structured layers of the hippocampus and olfactory bulbs that may contribute to early hippocampal synaptic deficits and olfactory dysfunction in AD mice. Spatially resolved transcriptomics was used to identify high-confidence genes that were differentially regulated in AD mice relative to controls. A diverse set of genes that modulate stress responses and transcription were predominant in both hippocampi and olfactory bulbs. Notably, we identify Bok, implicated in mitochondrial physiology and cell death, as a spatially downregulated gene in the hippocampus of mouse and human AD brains. In summary, we provide a rich resource of spatially differentially expressed genes, which may contribute to understanding AD pathology